Km Logan

Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1

In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titers were measured in 20 healthy volunteers. Dendritic cells (DCs) from these individuals were pulsed with replication defective Ad5 or Ad11 and co-cultured with autologous lymphocytes. Cytokine profiles, proliferative capacity, mucosal migration potential, and susceptibility to HIV infection of the adenovirus-stimulated memory CD4 T cells were measured. Stimulation of T cells from healthy Ad5-seropositive but Ad11-seronegative individuals with Ad5, or serologically distinct Ad11 vectors induced preferential expansion of adenovirus memory CD4 T cells expressing α4β7 integrins and CCR9, indicating a mucosal-homing phenotype. CD4 T-cell proliferation and IFN-γ production in response to Ad stimulation correlated with Ad5 antibody titers. However, Ad5 serostatus did not correlate with total cytokine production upon challenge with Ad5 or Ad11. Expanded Ad5 and Ad11 memory CD4 T cells showed an increase in CCR5 expression and higher susceptibility to infection by R5 tropic HIV-1. This suggests that adenoviral-based vaccination against HIV-1 in individuals with preexisting immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition.

Effect of breastfeeding compared with formula feeding on infant body composition: a systematic review and meta-analysis

BACKGROUND Early-life nutrition may influence later body composition. The effect of breastfeeding and formula feeding on infant body composition is uncertain. OBJECTIVE We conducted a systematic review and meta-analysis of studies that examined body composition in healthy, term infants in relation to breastfeeding or formula feeding. DESIGN PubMed was searched for human studies that reported the outcomes fat-free mass, fat mass, or the percentage of fat mass in breastfed and formula-fed infants. Bibliographies were hand searched, and authors were contacted for additional data. The quality of studies was assessed. Differences in outcomes between feeding groups were compared at prespecified ages by using fixed-effects analyses except when heterogeneity indicated the use of random-effects analyses. RESULTS We identified 15 studies for inclusion in the systematic review and 11 studies for inclusion in the meta-analysis. In formula-fed infants, fat-free mass was higher at 3-4 mo [mean difference (95% CI): 0.13 kg (0.03, 0.23 kg)], 8-9 mo [0.29 kg (0.09, 0.49 kg)], and 12 mo [0.30 kg (0.13, 0.48 kg)], and fat mass was lower at 3-4 mo [-0.09 kg (-0.18, -0.01 kg)] and 6 mo [-0.18 kg (-0.34, -0.01 kg)] than in breastfed infants. Conversely, at 12 mo, fat mass was higher in formula-fed infants [0.29 kg (-0.03, 0.61 kg)] than in breastfed infants. CONCLUSION Compared with breastfeeding, formula feeding is associated with altered body composition in infancy.

The diabetic pregnancy and offspring BMI in childhood: a systematic review and meta-analysis.

Aims/hypothesisOffspring of mothers with diabetes are at increased risk of metabolic disorders in later life. Increased offspring BMI is a plausible mediator. We performed a systematic review and meta-analysis of studies examining offspring BMI z score in childhood in relation to maternal diabetes.MethodsPapers reporting BMI z scores for offspring of diabetic (all types, and pre- and during-pregnancy onset) and non-diabetic mothers were included. Citations were identified in PubMed; bibliographies of relevant articles were hand-searched and authors contacted for additional data where necessary. We compared offspring BMI z score with and without adjustment for maternal pre-pregnancy BMI. We performed fixed effect meta-analysis except where significant heterogeneity called for use of a random effects analysis.ResultsData were available from nine studies. In the diabetic group unadjusted mean offspring BMI z score was 0.28 higher (all diabetic mothers vs controls (95% CI 0.09, 0.47; p = 0.004; nine studies; offspring of diabetic mothers n = 927, controls n = 26,384) and with adjustment for maternal pre-pregnancy BMI, 0.07 higher (95% CI −0.15, 0.28; p = 0.54; three studies; offspring of diabetic mothers n = 244, controls n = 11,206). There was no evidence of a difference in offspring BMI z score in relation to type of diabetes (gestational vs type 1, p = 0.95).Conclusions/interpretationMaternal diabetes is associated with increased offspring BMI z score, although this is no longer apparent after adjustment for maternal pre-pregnancy BMI in the limited number of studies in which this is reported. Causal mediators of the effect of maternal diabetes on offspring outcomes remain to be established; we recommend that future research includes adjustment for maternal pre-pregnancy BMI.

Avoiding sedation in research MRI and spectroscopy in infants: our approach, success rate and prevalence of incidental findings

Performing magnetic resonance investigations in a paediatric population can be difficult; image acquisition is commonly complicated by movement artefact and non-compliance. Sedation is widely used for clinically indicated investigations, but there is controversy when used for research imaging. Over a 10-year period we have performed whole body MRI on over 450 infants and hepatic magnetic resonance spectroscopy on over 270 infants. These investigations have been accomplished without the use of sedation in infants up to 3 months of age. Our overall success rate in achieving good quality images free of movement artefact is 94%. The prevalence of incidental findings on whole body (excluding brain) MRI in our cohort was 0.8%. We conclude that the use of sedation for research MRI in this group is not necessary. Our approach to MRI in infancy is also described.

Diabetes in pregnancy and infant adiposity: systematic review and meta-analysis

Objective Maternal glycaemia and anthropometry-derived newborn adiposity are strongly correlated. The children of mothers with diabetes are at greater risk of adverse metabolic health, and increased adiposity is a plausible mediator. We undertook a systematic review and meta-analysis to compare adiposity in infants of diabetic mothers (IDM) and infants of mothers without diabetes (NIDM). Design We identified observational studies reporting adiposity in IDM and NIDM. We searched references, traced forward citations and contacted authors for additional data. We considered all body composition techniques and compared fat mass, fat-free mass, body fat % and skinfold thickness. We used random effects meta-analyses and performed subgroup analyses by maternal diabetes type (type 1, type 2 and gestational) and infant sex. We examined the influence of pre-pregnancy body mass index (BMI) and conducted sensitivity analyses. Results We included data from 35 papers and over 24 000 infants. IDM have greater fat mass than NIDM (mean difference (95% CI)): 83 g (49 to 117). Fat mass is greater in infants of mothers with gestational diabetes: 62 g (29 to 94) and type 1 diabetes: 268 g (139 to 397). Insufficient studies reported data for type 2 diabetes separately. Compared with NIDM, fat mass was greater in IDM boys: 87 g (30 to 145), but not significantly different in IDM girls: 42 g (−33 to 116). There was no attenuation after adjustment for maternal BMI. Conclusions IDM have significantly greater adiposity in comparison with NIDM. These findings are justification for studies to determine whether measures to reduce infant adiposity will improve later health.

Development of Early Adiposity in Infants of Mothers With Gestational Diabetes Mellitus

OBJECTIVE Infants born to mothers with gestational diabetes mellitus (GDM) are at greater risk of later adverse metabolic health. We examined plausible candidate mediators, adipose tissue (AT) quantity and distribution and intrahepatocellular lipid (IHCL) content, comparing infants of mothers with GDM and without GDM (control group) over the first 3 postnatal months. RESEARCH DESIGN AND METHODS We conducted a prospective longitudinal study using MRI and spectroscopy to quantify whole-body and regional AT volumes, and IHCL content, within 2 weeks and 8–12 weeks after birth. We adjusted for infant size and sex and maternal prepregnancy BMI. Values are reported as the mean difference (95% CI). RESULTS We recruited 86 infants (GDM group 42 infants; control group 44 infants). Mothers with GDM had good pregnancy glycemic control. Infants were predominantly breast-fed up to the time of the second assessment (GDM group 71%; control group 74%). Total AT volumes were similar in the GDM group compared with the control group at a median age of 11 days (−28 cm3 [95% CI −121, 65], P = 0.55), but were greater in the GDM group at a median age of 10 weeks (247 cm3 [56, 439], P = 0.01). After adjustment for size, the GDM group had significantly greater total AT volume at 10 weeks than control group infants (16.0% [6.0, 27.1], P = 0.002). AT distribution and IHCL content were not significantly different at either time point. CONCLUSIONS Adiposity in GDM infants is amplified in early infancy, despite good maternal glycemic control and predominant breast-feeding, suggesting a potential causal pathway to later adverse metabolic health. Reduction in postnatal adiposity may be a therapeutic target to reduce later health risks.

Adiposity and hepatic lipid in healthy full-term, breastfed, and formula-fed human infants: a prospective short-term longitudinal cohort study

BACKGROUND The effect of mode of infant feeding on adiposity deposition is not fully understood. OBJECTIVE The objective was to test the hypothesis that differences in total and regional adipose tissue content and intrahepatocellular lipid (IHCL) arise in early infancy between breast- and formula-fed infants and to describe longitudinal changes. DESIGN This prospective longitudinal cohort study was performed in 2 hospitals in the United Kingdom. Healthy, full-term, appropriate weight-for-gestational age infants were recruited; adipose tissue volume and distribution were directly quantified by using whole-body magnetic resonance imaging; IHCL was assessed by in vivo proton magnetic resonance spectroscopy. Measurements were performed after birth (median age: 13 d) and at 6-12 wk of age. Method of infant feeding was recorded prospectively by using maternally completed feeding diaries. Breastfed was defined as >80% of feeds consisting of breast milk at both points; formula-fed was defined as >80% of feeds consisting of formula milk at both points. RESULTS Longitudinal results were obtained from 70 infants (36 breastfed, 9 mixed-fed, and 25 formula-fed). No differences were found in total or regional adipose tissue or IHCL between breastfed and formula-fed infants. In pooled analyses including all feeding groups, IHCL and total adipose tissue approximately doubled between birth and 6-12 wk: IHCL after birth (median: 0.949; IQR: 0.521-1.711) and at 6-12 wk (1.828; 1.376-2.697; P < 0.001) and total adipose tissue after birth (0.749 L; 0.620-0.928 L) and at 6-12 wk (1.547 L; 1.332-1.790 L; P < 0.001). Increasing adiposity was characterized by greater relative increases in subcutaneous than in internal adipose tissue depots. CONCLUSIONS No differences were detectable in adipose tissue or IHCL accretion between breastfed and formula-fed infants up to 2 mo. The substantial increase in IHCL seen over this period in both breastfed and formula-fed infants is a novel observation, which suggests that hepatic storage of lipids may be physiologic up to 2 mo. This trial was registered at www.clinicaltrials.gov as NCT02033005.

Fragmentation of SIV-gag Vaccine Induces Broader T Cell Responses

Background High mutation rates of human immunodeficiency virus (HIV) allows escape from T cell recognition preventing development of effective T cell vaccines. Vaccines that induce diverse T cell immune responses would help overcome this problem. Using SIV gag as a model vaccine, we investigated two approaches to increase the breadth of the CD8 T cell response. Namely, fusion of vaccine genes to ubiquitin to target the proteasome and increase levels of MHC class I peptide complexes and gene fragmentation to overcome competition between epitopes for presentation and recognition. Methodology/Principal Findings Three vaccines were compared: full-length unmodified SIV-mac239 gag, full-length gag fused at the N-terminus to ubiquitin and 7 gag fragments of equal size spanning the whole of gag with ubiquitin-fused to the N-terminus of each fragment. Genes were cloned into a replication defective adenovirus vector and immunogenicity assessed in an in vitro human priming system. The breadth of the CD8 T cell response, defined by the number of distinct epitopes, was assessed by IFN-γ-ELISPOT and memory phenotype and cytokine production evaluated by flow cytometry. We observed an increase of two- to six-fold in the number of epitopes recognised in the ubiquitin-fused fragments compared to the ubiquitin-fused full-length gag. In contrast, although proteasomal targeting was achieved, there was a marked reduction in the number of epitopes recognised in the ubiquitin-fused full-length gag compared to the full-length unmodified gene, but there were no differences in the number of epitope responses induced by non-ubiquitinated full-length gag and the ubiquitin-fused mini genes. Fragmentation and ubiquitination did not affect T cell memory differentiation and polyfunctionality, though most responses were directed against the Ad5 vector. Conclusion/Significance Fragmentation but not fusion with ubiquitin increases the breadth of the CD8 T vaccine response against SIV-mac239 gag. Thus gene fragmentation of HIV vaccines may maximise responses.

Sexual dimorphism in relation to adipose tissue and intrahepatocellular lipid deposition in early infancy

Sexual dimorphism in adiposity is well described in adults, but the age at which differences first manifest is uncertain. Using a prospective cohort, we describe longitudinal changes in directly measured adiposity and intrahepatocellular lipid (IHCL) in relation to sex in healthy term infants. At median ages of 13 and 63 days, infants underwent quantification of adipose tissue depots by whole-body magnetic resonance imaging and measurement of IHCL by in vivo proton magnetic resonance spectroscopy. Longitudinal data were obtained from 70 infants (40 boys and 30 girls). In the neonatal period girls are more adipose in relation to body size than boys. At follow-up (median age 63 days), girls remained significantly more adipose. The greater relative adiposity that characterises girls is explained by more subcutaneous adipose tissue and this becomes increasingly apparent by follow-up. No significant sex differences were seen in IHCL. Sex-specific differences in infant adipose tissue distribution are in keeping with those described in later life, and suggest that sexual dimorphism in adiposity is established in early infancy.

360 Sex Differences in Adipose Tissue Quantity and Distribution in Newborn Infants

Background and Aims Adipose tissue (AT) quantity and distribution influence metabolic health. In adult life women have greater total and subcutaneous AT, but men have greater internal abdominal AT (Gender Medicine, 2009; 6: 60–75). We aimed to explore AT volume and distribution in newborn male and female infants using magnetic resonance imaging (MRI). Methods A retrospective observational study was performed, using an existing database of neonatal body composition data, to compare male and female healthy term infants. Results Abstract 360 Table 1 Anthropometry at scan in male and female infants Measurement; mean (SD) Male (n=95) Female (n=90) p value Weight (g) 3590 (456) 3475 (496) 0.104 Length (cm) 53.0 (2.2) 52.7 (2.8) 0.435 Head circumference (cm) 36.4 (1.3) 35.8 (1.3) 0.002 Abstract 360 Table 2 AT volume in male and female infants AT volume (ml); mean [95% CI], after adjustment for scan weight Male (n=95) Female (n=90) p value Total AT 746 [718, 774] 841 [812, 869] <0.001 Abdominal superficial subcutaneous AT (SSAT) 102 [97, 107] 122 [117, 128] <0.001 Non-abdominal SSAT 540 [519, 560] 606 [586, 627] <0.001 Abdominal deep subcutaneous AT (DSAT) 14 [13, 15] 18 [17, 20] <0.001 Non-abdominal DSAT 12 [11, 13] 13 [12, 14] 0.008 Abdominal internal AT (IAT) 22 [20, 24] 21 [20, 23] 0.672 Non-abdominal IAT 56 [53, 60] 59 [55, 63] 0.310 Conclusions Female newborn infants have higher total and subcutaneous AT, but similar internal abdominal AT compared to males. Longitudinal study is required to assess gender specific alterations in AT distribution during infancy and childhood, and may identify possible influences of internal abdominal AT development in males.